ACE2-targeting monoclonal antibody as potent and broad-spectrum coronavirus blocker

Yuning Chen; Ya-Nan Zhang; Renhong Yan; Guifeng Wang; Yuanyuan Zhang; Zhe-Rui Zhang; Yaning Li; Jianxia Ou; Wendi Chu; Zhijuan Liang; Yongmei Wang; Yi-Li Chen; Ganjun Chen; Qi Wang; Qiang Zhou; Bo Zhang; Chunhe Wang

doi:10.1038/s41392-021-00740-y

ACE2-targeting monoclonal antibody as potent and broad-spectrum coronavirus blocker

Signal Transduct Target Ther. 2021 Aug 25;6(1):315. doi: 10.1038/s41392-021-00740-y.

Authors

Yuning Chen^#^{1

2}, Ya-Nan Zhang^#^{2

3}, Renhong Yan^#⁴, Guifeng Wang^#¹, Yuanyuan Zhang⁴, Zhe-Rui Zhang^{2

3}, Yaning Li⁵, Jianxia Ou⁶, Wendi Chu^{1

2}, Zhijuan Liang^{1

2}, Yongmei Wang^{1

2}, Yi-Li Chen^{7

8}, Ganjun Chen⁷, Qi Wang¹, Qiang Zhou⁹, Bo Zhang^{10

11}, Chunhe Wang^{12

13

14

15

16}

Affiliations

¹ Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
² University of Chinese Academy of Sciences, Beijing, China.
³ Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-ScienceChinese Academy of Sciences, Wuhan, Hubei, China.
⁴ Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, and Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
⁵ Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
⁶ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
⁷ Dartsbio Pharmaceuticals, Zhongshan, Guangdong, China.
⁸ Fudan University, School of Pharmacy, Shanghai, China.
⁹ Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, and Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China. zhouqiang@westlake.edu.cn.
¹⁰ Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-ScienceChinese Academy of Sciences, Wuhan, Hubei, China. zhangbo@wh.iov.cn.
¹¹ Drug Discovery Center for Infectious Disease, Nankai University, Tianjin, China. zhangbo@wh.iov.cn.
¹² Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. wangc@simm.ac.cn.
¹³ University of Chinese Academy of Sciences, Beijing, China. wangc@simm.ac.cn.
¹⁴ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. wangc@simm.ac.cn.
¹⁵ Dartsbio Pharmaceuticals, Zhongshan, Guangdong, China. wangc@simm.ac.cn.
¹⁶ Fudan University, School of Pharmacy, Shanghai, China. wangc@simm.ac.cn.

^# Contributed equally.

Abstract

The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 "knock-in" mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and "alanine walk" studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and "broad-spectrum" management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2 / antagonists & inhibitors*
Angiotensin-Converting Enzyme 2 / immunology
Animals
Antibodies, Monoclonal, Murine-Derived / immunology
Antibodies, Monoclonal, Murine-Derived / pharmacology*
Antiviral Agents / immunology
Antiviral Agents / pharmacology*
COVID-19 Drug Treatment*
Chlorocebus aethiops
Disease Models, Animal
HEK293 Cells
Humans
Mice
Mice, Inbred BALB C
Mice, Transgenic
SARS-CoV-2 / immunology*
Vero Cells

Substances

Antibodies, Monoclonal, Murine-Derived
Antiviral Agents
ACE2 protein, human
Angiotensin-Converting Enzyme 2